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ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents.
- Source :
-
JCI insight [JCI Insight] 2020 Sep 17; Vol. 5 (18). Date of Electronic Publication: 2020 Sep 17. - Publication Year :
- 2020
-
Abstract
- Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.
- Subjects :
- Animals
Apoptosis
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal pathology
Cell Nucleus drug effects
Cell Proliferation
DNA Repair
Female
Humans
Mice
Mice, Inbred BALB C
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Protein Transport
Sumoylation
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Basic Helix-Loop-Helix Transcription Factors antagonists & inhibitors
Carcinoma, Pancreatic Ductal drug therapy
Cell Nucleus metabolism
DNA Damage
Gene Expression Regulation, Neoplastic drug effects
Neoplasm Proteins antagonists & inhibitors
Pancreatic Neoplasms drug therapy
Piperazines pharmacology
Thiazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 5
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 32780723
- Full Text :
- https://doi.org/10.1172/jci.insight.138117